BF-1 interferes with transforming growth factor β signaling by associating with Smad partners
BF-1 interferes with transforming growth factor β signaling by associating with Smad partners
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DOI：
10.1128/mcb.20.17.6201-6211.2000
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Lai, E
中科院分区：
文献类型：
--
作者：
Dou, CL;Lee, J;Lai, E
有翼螺旋(WH)BF-1基因编码脑因子1(BF-1)(又称FOXG1)，对大脑皮层祖细胞的增殖是必不可少的。在这里，我们发现BF-1缺陷的端脑前体细胞更容易在转化生长因子-β(TGF-β)和激活素的作用下离开细胞周期。我们发现BF-1在体外的异位表达抑制了转化生长因子-β介导的生长抑制和转录激活。令人惊讶的是，我发现BF-1作为转化生长因子-β拮抗剂的能力并不需要它的DNA结合活性。因此，我们研究了BF-1是否可以通过与Smads或Smad结合伙伴相互作用来抑制Smad依赖的转录反应。我们发现BF-1不与Smads相互作用。由于介导TGP-β抑制生长的Smad伙伴的身份尚未明确，我们研究了一个已知由激活素和转化生长因子-β通过Smads和WH因子fast-2激活的模型报告系统。我们证明BF-1与FAST-2相关，这种相互作用依赖于相同的蛋白质区域，该区域介导其干扰转化生长因子-β的抗增殖活性和依赖于转化生长因子-β的转录激活。此外，FAST-2与BF-1的相互作用是由FAST-2与Smad2相互作用所需的相同结构域介导的。我们提出了一个模型，在这个模型中，BF-1通过与FAST-2或其他DNA结合蛋白相互作用来干扰对转化生长因子-β的转录反应，这些蛋白作为Smad2的伙伴发挥作用，并与Smad2具有共同的相互作用模式。
The winged-helix (WH) BF-1 gene, which encodes brain factor 1 (BF-1) (also known as foxg1), is essential for the proliferation of the progenitor cells of the cerebral cortex. Here we show that BF-1-deficient telencephalic progenitor cells are more apt to leave the cell cycle in response to transforming growth factor beta (TGF-beta) and activin. We found that ectopic expression of BF-1 in vitro inhibits TGF-beta mediated growth inhibition and transcriptional activation. Surprisingly, me found that the ability of BF-1 to function as a TGF-beta antagonist does not require its DNA binding activity. Therefore, we investigated whether BF-1 can inhibit Smad-dependent transcriptional responses by interacting with Smads or Smad binding partners. We found that BF-1 does not interact with Smads. Because the identities of the Smad partners mediating growth inhibition by TGP-beta are not clearly established, we examined a model reporter system which is known to be activated by activin and TGF-beta through Smads and the WH factor FAST-2. We demonstrate that BF-1 associates with FAST-2, This interaction is dependent on the same region of protein which mediates its ability to interfere with the antiproliferative activity of TGF-beta and with TGF-beta-dependent transcriptional activation. Furthermore, the interaction of FAST-2 with BF-1 is mediated by the same domain which is required for FAST-2 to interact with Smad2. We propose a model in which BF-1 interferes with transcriptional responses to TGF-beta by interacting with FAST-2 or with other DNA binding proteins which function as Smad2 partners and which have a common mode of interaction with Smad2.